Millions of babies have been born via in vitro fertilization (IVF), and researchers are just starting to document some of the lasting effects the process may have on early development.

The ability to shift fertilization into a lab dish has revolutionized infertility treatment, and rewritten some of the basic tenets of reproduction. But does IVF make children more vulnerable to certain cognitive or other developmental issues? In the largest study to date looking at the connection between IVF procedures and neurological disorders, scientists found a small but significant risk of intellectual disabilities among twins and triplets, though not among singleton births.

The researchers studied 2.5 million Swedish children, and compared those born via IVF with those who were conceived naturally. About 47 in 100,000 infants born from IVF developed cognitive deficits, such as low IQ or problems in communicating or socializing with others, compared with 40 in 100,000 among naturally conceived children.

“For IVF there are known risks already, such as birth defects and cancer, and now mental retardation should perhaps be added,” says the study’s lead author Sven Sandin of King’s College in London.

Specific procedures, such as IVF that involved more manipulation of the sperm to promote fertilization, were more likely to be associated with higher rates of neurological issues than IVF without it. That suggests that male-based fertility issues may have a stronger correlation with later cognitive deficits. “That brings us to consider that there might be some genetics involved in severe male-factor [infertility], but it is extremely important for my patients with male-factor [infertility] not to freak out and think they are the significant risk. The total number of babies with problems with IVF, and even male factor, are small,” says Dr. Avner Hershlag, chief of the Center for Human Reproduction at North Shore University Hospital in Manhasset, N.Y., who was not involved with the study.

In addition, when the scientific team focused just on singleton births, the link to intellectual deficits was no longer significant. That confirms previous studies that identified a greater risk of birth defects and developmental problems among multiple births, which are more common with IVF since doctors often transfer several embryos during a cycle, to improve a woman’s chances of becoming pregnant. “I call it the epidemic of multiple births that our field has created by transferring multiple embryos into the uterus. It has brought up a lot of medical and health issues for the babies as well as for the moms,” says Hershlag. To avoid the added risks associated with multiple births, many centers now only transfer one to three embryos at a time.

Other improvements in the IVF process may also reduce any added risks that the procedure could pose for development. Doctors now have more sophisticated ways of identifying the most robust embryos for transfer, and are able to manipulate the timing of fertilization to better mimic natural conception.

Still, with the first babies born through IVF now reaching their mid-30s, more studies are examining what the lasting legacy of IVF might be. In October, research presented at the American Academy of Pediatrics National Conference and Exhibition in New Orleans found that among 4,795 babies born after IVF and 46,025 infants who were conceived naturally, 3,463 babies developed congenital birth defects. But that doesn’t necessarily mean that the IVF treatments are responsible. In a study from March, for example, researchers reported that neurological problems among IVF babies were more likely brought about by factors related to infertility and not the treatments themselves.

Sandin says despite the slightly increased relative risk he and his team found when comparing IVF and naturally conceived children, the absolute risk of problems with IVF remain small. And most of the added problems appeared to be associated with certain infertility procedures. “The risk should however be considered, together with the clinician, to be treatment-specific,” he says.

About 5 million kids worldwide have been born from IVF, says Hershlag, and most are healthy. “I am not aware of a case of mental retardation or autism in babies resulting from our treatment,” he says. “However, this study is very welcome because it is a very significant attempt to answer some important questions.” Sandin hopes the results will trigger more studies into the longer-term effects of IVF on a range of health issues. Based on the available data, “in general we tell parents that IVF is safe and to a large degree, babies born from IVF are healthy and grow into healthy adults,” says Hershlag. With more studies, however, this reassurance can be backed by even more solid scientific evidence.